July 16, 2012 – The FDA’s Office of Prescription Drug Promotion (OPDP) is on pace to deliver the same number of enforcement letters it sent out in 2011, having issued 15 Warning or Untitled Letters to date in 2012. OPDP had issued 17 such letters by this point in 2011.

The seven enforcement letters sent out by OPDP since May 1 were issued for alleged violations relating to a television ad, a branded story, a journal ad, a Web page, a patient brochure and two video segments. OPDP discovered problems with these promotional materials as a result of routine surveillance and monitoring (1), review of materials under Form FDA-2253 (5) and via a complaint received under the agency’s “Bad Ad” program (1).

In a May 25 Warning Letter, OPDP charges that a Pfizer Inc. TV ad for EPIPEN and EPIPEN JR. is false and misleading because it overstates the efficacy of the products. Specifically, the agency took issue with the “overwhelming impression” created by the ad that the EpiPen alone could provide assurance that a child with life-threatening allergic reactions does not need to worry or take precautionary measures to avoid exposure to allergens, according to OPDP. “This violation is particularly alarming from a public health perspective because the misleading presentation of the use of EpiPen may result in serious consequences, including death,” the Warning Letter states.

An Untitled Letter sent to Vertex Pharmaceuticals Inc. on May 25 found fault with a branded story that the company submitted to OPDP for INCIVEK Film Coated Tablets. The letter states that although claims made in the branded story may be an accurate reflection of the story subject’s experience with hepatitis C and treatment with Incivek, it misleadingly implies that most or all similar patients will achieve the same results. “One patient’s treatment response does not constitute substantial evidence,” OPDP states in the letter, which also cited Vertex for omission of material fact and minimization of risk information.

OPDP objected to a journal ad for Watson Pharmaceuticals Inc.’s NULECIT due to unsubstantiated claims, according to a June 7 Untitled Letter. OPDP alleges that the journal ad claims there is a reduced need for erythropoiesis-stimulating agents (ESAs) with Nulecit use and that there are significant cost savings when the drug is added to ESA therapy. 

As part of its routine monitoring and surveillance, OPDP reviewed an “efficacy” Web page for KEPIVANCE and found it to be false or misleading because “it omits and minimizes important risk information and makes misleading efficacy claims.” The June 7 Untitled Letter, sent to Quintiles Inc. as the U.S. agent for Swedish Orphan Biovitrum AB, states that although the Web page links to the Prescribing Information and the Kepivance Safety and Tolerability sections of the Web site (which includes the drug’s risk information), “these links are not sufficient to mitigate the misleading impression created by the omission.” OPDP also alleges that the Kepivance Web page included misleading efficacy claims and that the promotional Web pages were not submitted to OPDP using Form FDA-2253.

A June 19 Untitled Letter to Pfizer cited a patient brochure for ZMAX, which it alleged is false or misleading because it:

• Omits and minimizes important risk information
• Makes unsubstantiated superiority claims
• Omits material facts
• Broadens the indication for the product
• Makes misleading efficacy claims
• Makes unsubstantiated claims.

For example, OPDP states that the Zmax brochure “minimizes the risks associated with Zmax by failing to disclose that severe and fatal allergic and skin reactions have been observed with azithromycin.” Even though the brochure states that patients should seek emergency help right away if they develop a series of severe side effects, such as trouble swallowing, hives, swelling of the face or tongue or trouble breathing, “failure to disclose the severity of the potentially fatal allergic reactions, including recurrence of the allergic symptoms even when the drug was discontinued … misleadingly minimizes the risks associated with Zmax,” OPDP states in the letter.

Finally, two Untitled Letters – both sent on June 21 – address testimonials in promotional video segments. An Untitled Letter sent to Acorda Therapeutics Inc. states that a video for AMPYRA Extended Release Tablets is false or misleading because it overstates the efficacy of the drug product and minimizes important risk information. In the video, a patient discusses her experience with and treatment for multiple sclerosis and makes statements that may reflect her personal experience, but are not supported by substantial evidence, according to OPDP.

The letter to Acorda also states that statements made in the testimonial minimize risks associated with Ampyra. “Specifically, they imply that patients who experience adverse events, such as paresthesia and insomnia, will be ‘able to get used to it’ and such adverse events will disappear within a month,” the letter states, and “the overall effect of the risk presentation undermines the communication” of important risk information.

In its Untitled Letter to Valeant Pharmaceuticals North America, OPDP alleges that a patient assessment video and a Web page for XENAZINE Tablets for Oral Use are false and misleading because they overstate efficacy, omit material facts and omit and minimize the serious risks of the drug.

The video, in which a case study of one patient is presented showing “before and after” shots, overstates the product’s efficacy, the letter states. These presentations “are misleading because they suggest that treatment with Xenazine will lead

to significant improvements in balance, walking and postural stability in patients with Huntington’s disease, when such benefits have not been demonstrated by substantial evidence,” the letter states.

OPDP also takes issue with the nearly four-minute video presenting many claims regarding the efficacy of Xenazine while minimizing its risks and “failing to convey any risks associated with Xenazine during this audio-visual presentation” (emphasis original). The letter also states that the video seemingly ignores the boxed warning, contraindications, warnings and precautions associated with the drug. Further, the Web page where the patient assessment video is located “completely omits the risk of clinical worsening and adverse effects associated with Xenazine and the increased risk of somnolence and sedation with concomitant use of alcohol or other sedating drugs.”

Several of the letters issued during this period echo problems cited by OPDP in the first quarter of 2012. In an enforcement update held at the end of April, OPDP Regulatory Counsel Ernest Voyard clarified that patient case studies used for promotional purposes should reflect the general use of the product as listed in the PI. “Companies shouldn’t pick extreme cases that show a clear benefit and hide the risk. It should be an accurate reflection of what patients should expect,” he said. “That being said, it doesn’t have to be a middle-of-the-road patient either, but it should reflect what’s expected.”

Case studies focusing on outlier patients are “probably dangerous,” Voyard noted. “The exceptional patient is an outlier, and any outlier can be problematic,” he said. “A [case study] patient has to experience some of the benefits and some of the risks – not necessarily every benefit and every risk

– but the [case study patient] should address the general experience.”